Comparison of effects of pioglitazone and glimepiride on plasma soluble RAGE and RAGE expression in peripheral mononuclear cells in type 2 diabetes: Randomized controlled trial (PioRAGE)

Objective: The receptor for advanced glycation end-products (RAGE) is involved in vascular complications in diabetic patients. Pioglitazone, in contrast to glimepiride, has been shown to be protective against atherosclerotic disorders. In this study, we directly compared the effects of those drugs on RAGE system. Methods: Sixty-three type 2 diabetic patients (age 20-80 years, hemoglobin A1c 6.4-10.3%) being treated with sulfonylurea (glimepiride 0.5-2.0 mg/day, glyclazide 20-80 mg/day, glibenclamide 1.25-5.0 mg/day), or with nateglinide or metiglynide were randomly assigned to receive either pioglitazone (n = 31) or glimepiride (n = 32). Levels in plasma of soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE), and RAGE expression in peripheral mononuclear cells were determined at 0, 12, and 24 weeks. Results: Twenty-seven patients in the pioglitazone group (15-30 mg) and 30 in the glimepiride group (0.5-4 mg) completed the 24-week trial. Increases in plasma esRAGE were significantly greater in the pioglitazone group (12 weeks: 55 +/- 15 pg/mL, p = 0.018; 24 weeks: 90 +/- 14 pg/mL, p = 0.003) as compared to the glimepiride group (12 weeks: 12 +/- 9 pg/mL; 24 weeks: 29 +/- 14 pg/mL). Increases in plasma sRAGE were also significantly (p = 0.037) higher in the pioglitazone group at 24 weeks (170 +/- 166 vs. 74 +/- 171 pg/mL). Furthermore, RAGE expression in mononuclear cells was significantly (p = 0.008) decreased to a greater degree in the pioglitazone group at 24 weeks (-7.39 +/- 5.18 vs. -3.39 +/- 5.72 MFI). Changes in HbA1c, IRI, and insulin resistance index (HOMA) at 24 weeks were not significantly different between the groups. Conclusion: Pioglitazone suppresses RAGE expression and increases circulating sRAGE/esRAGE, and those activities are not necessarily dependent on plasma glucose or insulin resistance levels. Clinical trial No: UMIN000002055. (C) 2014 Elsevier Ireland Ltd. All rights reserved.